The following is provided as background information only and is not to be construed as prior art to the present invention.
Over the past three decades a variety of antibiotics have become available for clinical use. One class of antibiotics that has seen remarkable growth is the β-lactams, over 70 of which have entered clinical use since 1965. Unfortunately, the widespread use of these antibiotics has resulted in an alarming increase in the number of resistant strains, especially among clinically important bacteria such as the genera Salmonella, Enterobacteriaceæ, Pseudomonas and Staphylococcus. 
Bacterial resistance to cephalosporins occurs primarily through three mechanisms: (a) destruction of the antibiotic by β-lactamases; (b) decreased penetration due to changes in bacterial outer membrane composition; and (c) alteration of penicillin-binding proteins (PBPs) resulting in interference with β-lactam binding. The latter pathway is especially important, as the binding of β-lactams to PBPs is essential for inhibiting peptidoglycan biosynthesis (peptidoglycan is a required bacterial cell-wall component). Certain gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (“MRSA”) and various genus Enterococcus bacteria are highly resistant to beta-lactam antibiotics. The resistance of MRSA is due to the presence of a PBP called PBP2a, which binds very poorly to β-lactam antibiotics. The options for treating infection caused by MRSA are limited and there is a need for new antibiotics with activity against these strains.
In recent years, a novel family of β-lactam antibiotics, the carbacephems (1), has been sporadically touted as having promise against MRSAs and other resistant species. In compound (1), R1 and R2 are variously described as a wide range of aromatic and heteroaromatic entities. R3 has generally been reported as an optionally substituted alkyl group. For example,
in Ternansky, et al., J. Med. Chem., 1993, 1971, compounds of general structure (1), in which R1 is 2-amino-4-thiazolyl, R3 is 2-fluoroethyl and R2 is alternately 1,3,4-thiadiazol-2-yl(2), 6-nitrobenzothiazol-2-yl (3) or pyridino[3,4-d]thiazol-2-yl(4), are disclosed.

The problem with the above compounds and, presumably, the carbacephems in general, is that researchers investigating the family have been unable to achieve an acceptable balance between MRSA potency and serum protein binding. That is, MRSA activity was demonstrated relatively early on to correlate with lipophilicity; the more lipophilic the carbacephem, the greater its potency. Unfortunately, the greater the lipophilicity of the compound, the greater is its tendency toward high protein binding. Such binding is undesirable because it reduces the compound's bioavailability. In compounds (2), (3) and (4), for example, the peripheral fluoroethyl group was likely used in an attempt to circumvent the problem by affording some lipophilicity to the compound as a whole while maintaining a lower level of lipophilicity in the core molecule. The effort appears to have been unsuccessful since compound (2) exhibited a good MIC (2 μg/mL) but poor serum binding (>99.2%), compound (3) exhibited a fair MIC (4 μg/mL) but also showed poor serum binding (99.6%) and compound (4) exhibited excellent low, 36%, serum binding but an extremely poor MIC (64 μg/mL).
Despite the above, the carbacephems remain an intriguing approach to dealing with MRSA and other resistant bacterial species. What is needed, however, is a class of carbacephems that achieves the requisite balance of MRSA potency and protein binding. The present invention provides such a class of compounds.